Identification of Novel MAP Kinase Pathway Signaling Targets by Functional Proteomics and Mass Spectrometry

Lewis, Timothy S.; Hunt, John B.; Aveline, Lauren D.; Jonscher, Karen R.; Louie, Donna F.; Yeh, Jennifer M.; Nahreini, Theresa Stines; Resing, Katheryn A.; Ahn, Natalie G.

doi:10.1016/s1097-2765(00)00132-5

Cited by 234 publications

(183 citation statements)

References 50 publications

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“…However, this does not appear to explain the observations reported here. An approach used by Lewis et al (2000), examining the whole pattern of MAP kinase pathway signalling targets, could help to elucidate the molecular origins of the present observation of a radiosensitivity linked to high tumoural EGFR levels.…”

Section: Discussionmentioning

confidence: 99%

Sequence-dependent effects of ZD1839 (‘Iressa’) in combination with cytotoxic treatment in human head and neck cancer

et al. 2002

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Elevated levels of epidermal growth factor receptor in head and neck cancer have been extensively reported, and are correlated with poor prognosis. The combination of cisplatin and 5-fluorouracil is a standard treatment regimen for head and neck cancer, with radiation representing another therapeutic option. Six head and neck cancer cell lines were used to study the cytotoxic effects of combining ZD1839 ('Iressa'), a new selective epidermal growth factor receptor tyrosine kinase inhibitor, and radiation. Two of the cell lines were also used to study the combination of ZD1839 and cisplatin/5-fluorouracil. Cytotoxic effects were assessed by the MTT test. The results indicated that ZD1839 applied before radiation gave the best effects (P=0.002); an effect that was strongest in those p53-mutated cell lines that express the highest epidermal growth factor receptor levels. The effects of ZD1839 with cisplatin and/or 5-fluorouracil were sequence dependent (P50

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Section: Discussionmentioning

confidence: 99%

Sequence-dependent effects of ZD1839 (‘Iressa’) in combination with cytotoxic treatment in human head and neck cancer

et al. 2002

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“…Proteolysis of microphthalmia induced by sustained ERK1/2 is accompanied by a decrease in MKP-1 expression, which triggers melanocyte de-differentiation and transformation (36). On the other hand, MKK1/2-ERK1/2 signaling stimulates proteasomecatalyzed processing of hHR23B (47), which functions in the initiation step of nucleotide excision repair (48). Moreover, forced expression of constitutively active MKK1/2 can up-regulate a proteasome -chain protein, suggesting that this signaling may have a general role in regulating the proteasome machinery (47).…”

Section: Exogenous Mkp-1 Phosphatase Activity Decreases Erk Phosphorymentioning

confidence: 99%

ERK1/2 Achieves Sustained Activation by Stimulating MAPK Phosphatase-1 Degradation via the Ubiquitin-Proteasome Pathway

Lin

Chuang

Yang

2003

Journal of Biological Chemistry

119

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Sustained extracellular signal-regulated kinase 1/2 (ERK1/2) activation does not always correlate with its upstream Ras-Raf-mitogen-activated protein kinase kinase 1/2 (MKK1/2) signal cascade in cancer cells, and the mechanism remains elusive. Here we report a novel mechanism by which sustained ERK1/2 activation is established. We demonstrate that Pb(II), a carcinogenic metal, persistently induces ERK1/2 activity in CL3 human lung cancer cells and that Ras-Raf-MKK1/2 signaling cannot fully account for such activation. It is intriguing that Pb(II) treatment reduces mitogenactivated protein kinase phosphatase 1 (MKP-1) protein levels in time-and dose-dependent manners, which correlates with sustained ERK1/2 activation, and that Pb(II) also induces mRNA and de novo protein synthesis of MKP-1. In Pb ( Members of the family of mitogen-activated protein kinase (MAPK) 1 proteins are vital intracellular signaling components that become phosphorylated and activated in response to a wide diversity of extracellular stimuli, including growth factors, cytokines, and environmental stresses (reviewed in Refs. 1-5). MAPKs are activated through a three-kinase module composed of a MAPK, a MAPK kinase (MKK), and a MKK kinase (MKKK). These MAPK modules are connected to cell surface receptors and activated via interaction with a family of small GTPases and MKKK kinases. Activated MAPKs phosphorylate many substrates, including cytoskeletal proteins, other kinases, phosphatases, enzymes, and transcription factors, thereby orchestrating several cellular alterations including proliferation, differentiation, survival, and apoptosis. The duration and strength of MAPK activation also affects these biological outcomes. Three major MAPK subfamilies have been extensively studied, i.e. the extracellular signal-regulated kinases (ERK1/2), the c-Jun N-terminal kinases (JNKs), and the p38 kinases. Activation of a particular MAPK signal must be controlled with high specificity and efficiency to achieve precise physiological regulation. The recent discovery of specific docking sites among the members of the MAPK cascades provide a mechanism that explains how specific and efficient signaling is established. For instance, a cluster of positively charged amino acids followed by an LXL motif called the D domain (or the kinase interaction motif, KIM) has been identified in MKKs, MAPK phosphatases (MKPs), and several MAPK substrates (6 -8). The D domain binds specifically to an acidic domain (common docking domain) within a docking groove of MAPKs (6 -8). Another docking site found in many ERK substrates is called the DEF motif (docking site for ERK, FXFP) (8, 9). These docking interactions facilitate phosphorylation of substrates by MAPKs on specific Ser or Thr residues followed by a Pro residue ((S/T)P sites).The small GTPase, MKKK, and MKK in the ERK pathway are known to be Ras, Raf, and MKK1/2, respectively (1-5). Activation of ERK1/2 requires a dual-phosphorylation by MKK1/2 on the Thr and Tyr residues of TEY sites within the activation loop, wherea...

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“…Immobiline DryStrips (pH 3-10 nonlinear, 7 cm; Amersham Pharmacia Biotech, Piscataway, NJ) were loaded with 1 mg of the whole-cell extracts prepared with a 4% Nonidet P-40 solution similarly as described previously (14). Isoelectric focusing was performed at room temperature using an IPGphor electrophoresis unit (Amersham Pharmacia Biotech).…”

Section: D Gel Electrophoresis and Msmentioning

confidence: 99%

Cutting Edge: Induced Expression of a RhoA-Specific Guanine Nucleotide Exchange Factor, p190RhoGEF, Following CD40 Stimulation and WEHI 231 B Cell Activation

Lee

Kim

2003

The Journal of Immunology

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Stimulation of the B cell surface receptor CD40 induces transcriptional activation and protein expression. To determine which proteins are required for the CD40-mediated B cell activation, we performed a two-dimensional gel electrophoresis of the WEHI 231 B cell lysates. We report in this study the identification of one protein in which the expression was remarkably induced following CD40 stimulation. It was the p190 Rho guanine nucleotide exchange factor (GEF), p190RhoGEF, a recently identified GEF that is specific for RhoA. Overexpression of either p190RhoGEF or RhoA (Q63L), a constitutively active form of RhoA, mimics the effects of CD40 stimulation, such as changes in cellular structure and NF-κB activation. These p190RhoGEF overexpression effects are abrogated when coexpressed with a dominant negative form of RhoA (T19N). We also provide evidence for the CD40-mediated cellular changes that are abrogated in cells that are overexpressed with the dominant negative form of either p190RhoGEF (Y1003A) or RhoA (T19N).

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Identification of Novel MAP Kinase Pathway Signaling Targets by Functional Proteomics and Mass Spectrometry

Cited by 234 publications

References 50 publications

Sequence-dependent effects of ZD1839 (‘Iressa’) in combination with cytotoxic treatment in human head and neck cancer

Sequence-dependent effects of ZD1839 (‘Iressa’) in combination with cytotoxic treatment in human head and neck cancer

ERK1/2 Achieves Sustained Activation by Stimulating MAPK Phosphatase-1 Degradation via the Ubiquitin-Proteasome Pathway

Cutting Edge: Induced Expression of a RhoA-Specific Guanine Nucleotide Exchange Factor, p190RhoGEF, Following CD40 Stimulation and WEHI 231 B Cell Activation

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